cyclic-gmp and Infections

The presence and the role of nitric oxide synthase (NOS) were investigated in the molluscan hemocytes by immunocytochemical, biochemical and functional approaches. Using an anti-NOS polyclonal antibody, immunoreactivity was observed in the hemocytes, and this reactivity increased after stimulation of the animals with Escherichia coli, indicating that this enzyme is inducible. The NOS inducibility was also histochemically demonstrated by detection of NADPH-diaphorase activity. Biochemical studies show that the enzyme is 70% cytoplasmatic and 30% membrane bound and that the inducible form is mainly cytoplasmatic. The nitrite + nitrate and citrulline formation, the inhibition by N omega-nitro-L-arginine, the Km value for arginine, the calcium and co-enzyme dependence show that the molluscan NOS shares the same properties as the NOS isoenzymes so far studied. However, it cannot be identified with any of these enzymes. It appears to be in some way similar to an inducible form of human hepatocyte NOS. Also cytokines are able to induce NOS. In vitro studies have shown that hemocytes produce nitric oxide (NO), a bactericide substance, and that there is a relationship between the NO system and phagocytosis. The presence of NO in the invertebrate hemocyte demonstrates that critical molecules have been conserved over the course of evolution.

Topics: Animals; Cardiovascular Diseases; Cell Adhesion; Citrulline; Cyclic GMP; Endothelium, Vascular; Enzyme Activation; Humans; Infections; Nitric Oxide; Nitric Oxide Synthase; Nitrites; Vasodilation

Many cellular functions in eukaryotic pathogens are mediated by the cyclic nucleotide binding (CNB) domain, which senses second messengers such as cyclic AMP and cyclic GMP. Although CNB domain-containing proteins have been identified in many pathogenic organisms, an incomplete understanding of how CNB domains in pathogens differ from other eukaryotic hosts has hindered the development of selective inhibitors for CNB domains associated with infectious diseases. Here, we identify and classify CNB domain-containing proteins in eukaryotic genomes to understand the evolutionary basis for CNB domain functional divergence in pathogens. We identify 359 CNB domain-containing proteins in 31 pathogenic organisms and classify them into distinct subfamilies based on sequence similarity within the CNB domain as well as functional domains associated with the CNB domain. Our study reveals novel subfamilies with pathogen-specific variations in the phosphate-binding cassette. Analyzing these variations in light of existing structural and functional data provides new insights into ligand specificity and promiscuity and clues for drug design. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases.

Topics: Cyclic AMP; Cyclic GMP; Drug Design; Evolution, Molecular; Genome; Host-Pathogen Interactions; Humans; Infections; Phylogeny; Protein Binding; Protein Kinases; Protein Structure, Tertiary; Signal Transduction

Recently, heme oxygenase-carbon monoxide (HO-CO) pathway has been reported to be involved in the development of lipopolysaccharide (LPS) fever. However, no information exists about its participation in LPS tolerance, which is defined by an attenuation of the febrile response to repeated administrations of LPS. Thus, we tested the hypothesis that HO-CO pathway plays a role in endotoxin tolerance, which was induced by means of three consecutive LPS intraperitoneal injections (i.p.) at 24-h intervals. Body temperature (Tb) was measured by biotelemetry. Induction of the HO pathway using intracerebroventricular (i.c.v.) heme lysinate reversed tolerance, and this effect could be prevented by pretreatment with ODQ [a soluble guanylate cyclase (sGC) inhibitor; i.c.v.]. These results indicate that HO-CO pathway seems to be down-regulated during LPS tolerance, and that CO is the HO product that can prevent LPS tolerance, acting via cGMP. In further support, either biliverdine or iron (the others HO products; i.c.v.) had no effect in LPS-induced tolerance.

Topics: Animals; Biliverdine; Body Temperature; Carbon Monoxide; Chlorides; Cyclic GMP; Disease Models, Animal; Down-Regulation; Drug Tolerance; Endotoxins; Enzyme Inhibitors; Ferric Compounds; Fever; Guanylate Cyclase; Heme Oxygenase (Decyclizing); Infections; Inflammation Mediators; Injections, Intraperitoneal; Iron; Lipopolysaccharides; Male; Rats; Rats, Wistar; Signal Transduction

Occupational bronchial asthma with its prevalence amounting to 14% is one of the main entities in occupational morbidity structure. Clinical evidence in recent decades demonstrates changed phenotype of occupational bronchial asthma. Changes are increased number of patients suffering from the severe asthma, higher occurrence of occupational bronchial asthma which pathogenesis is more significantly mediated by nonimmune mechanisms. Prevalence of these types of occupational bronchial asthma approaches 9.7-22%.

Topics: Adenylyl Cyclases; Asthma; Cyclic AMP; Cyclic GMP; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Infections; Middle Aged; Occupational Diseases; Pituitary-Adrenal System